Peripheral arterial disease (PAD) is a complex illness causing a significant amount of pain and suffering, with an estimated 8-12 million cases in the United States. The elderly are particularly at risk, with a prevalence of approximately 20% in people greater than 75 years of age. Further, the number of cases is expected to increase as the population ages. PAD exerts significant effects on functional capacity, quality of life, productivity, and health care costs. This R21 Grant application was developed to address the genetic basis of PAD using existing and novel data sets and tissue samples. Recent sequencing of the human genome has opened up fertile areas of investigation for many human diseases. To date, there have been a limited number of studies that have investigated the genetic underpinnings of PAD. Fundamental advancements in our knowledge of the molecular pathophysiology of PAD utilizing genome technologies represents an unprecedented opportunity to develop new diagnostic, prognostic and therapeutic interventions for this disease. To address this problem, we have developed a unique research group that combines the collaborative expertise of vascular surgery, molecular cardiology, biostatistics, and human genetics. In this application we propose to investigate PAD using genomic methodology. We have assembled all of the necessary components with direct access to human peripheral arteries, a large clinical population with PAD, experience with gene expression profiling, and the advanced statistical analysis required to study this complex disease. Using this methodology, we propose to use expression genomic s on peripheral arterial tissue collected from limb amputations in patients with severe PAD. Using data derived from these arterial samples we will test the following hypotheses: 1. Gene expression profiles of peripheral arterial tissues can be used to identify molecular phenotypes of diseased arteries. 2. Various phenotypes of patients with PAD will have different patterns of gene expression. 3 Genes isolated from diseased peripheral arteries will differ from key genes that have been identified from existing data sets for central (aortic) atherosclerosis. To achieve these goals, the following specific aims will be pursued: 1. To isolate arterial tissue from amputated limbs and collect clinical data from these patients with severe PAD. 2. To perform gene expression analysis using microarrays on RNA extracted from harvested peripheral arterial tissues. 3. To apply statistical methods to identify gene expression patterns that correlate with the clinical phenotypes of patients with PAD and compare these expression patterns to existing identified genes of aortic atherosclerosis.